Project Summary Ten percent of patients with renal cell carcinoma will develop brain metastases. Patients frequently develop brain metastasis even while their extracranial disease remains under control. Unfortunately, treatment options are limited, and most current clinical trials in the US exclude patients with brain metastases. Our limited understanding of the molecular drivers of brain metastases has hampered the development of novel therapeutics for this common complication of cancer. Our group recently completed whole-exome sequencing of 104 brain metastases, primary tumors and normal tissue across many histologies. In this initial dataset, which included only eight brain metastases from renal cell carcinoma, we detected clinically actionable alterations that were unique to the brain metastases. We have now assembled a large cohort of renal cell carcinoma brain metastases. Our proposed genomic analysis will focus on characterizing the molecular alterations in brain metastases from RCC. We will analyze brain metastases, extracranial metastases, cerebrospinal fluid, and plasma samples before and after targeted therapy or immune checkpoint blockade therapy to identify genetic alterations driving their clinical behavior, including resistance to therapy. Identification of these mutations will aid in the design of more effective targeted treatments to treat brain metastases.